The objective of this proposal is to characterize the mechanisms mediated by the protein kalirin that control synaptic structural and functional plasticity in pyramidal neurons. Building upon data produced in the previous grant period, and using a novel mouse model we have recently generated, we will examine the role of an important molecular regulator of dendritic spine plasticity. As both spine density and kalirin expression are reduced in schizophrenic patients' brains, these studies are expected to provide important insight into the mechanisms of spine pathology in mental disorders. Modifications in spiny excitatory synapse structure and function modulate synaptic transmission and plasticity, and underlie cognitive functions. Conversely, altered spine plasticity contributes to the pathogenesis of several mental disorders. Hence, understanding the molecular mechanisms that control spiny synapse plasticity and pathology will provide essential insight into the neurobiology of cognitive functions and mental disorders that affect cognition. Synapse structure and function are controlled by a complex network of interactions between numerous proteins. Our previous studies have established the postsynaptic protein kalirin as an important regulator of synaptic structural plasticity. Importantly, kalirin has recently been implicated in several mental disorders including schizophrenia. Kalirin is a brain-specific guanine-nucleotide exchange factor which activates the small GTPase Rac1 and its most abundant form, kalirin-7, is highly enriched in spines. In the previous funding period we demonstrated that kalirin-7 plays an important role in activity-dependent synaptic structural and functional plasticity downstream of NMDA receptors and CaMKII. We have shown that kalirin also regulates AMPA receptors in spines, and mediates N-cadherin-dependent synaptic adhesion signaling. We have also generated a full knockout of the KALRN gene (KALRN-/-) in mice, and found that this results in a robust and cortex-specific reduction in Rac1 activation and in the number of functional spiny excitatory synapses. KALRN-/- mice have impairments in specific cognitive functions. In this proposal we will dissect the functional roles of kalirin signaling in spiny synapse morphogenesis and plasticity. We hypothesize that kalirin signaling plays crucial and specific roles in synapse function and spine stability/dynamics. We propose the following Specific Aims: 1) To characterize the mechanisms underlying kalirin-dependent regulation of AMPA receptor-mediated transmission and plasticity. 2) To chart the time course and characterize the mechanisms of kalirin-dependent spine stability and dynamics. 3) To characterize the role of kalirin signaling in N-cadherin-dependent spine morphogenesis in vivo. 1